The generation of virus-specific effector CD8 T cells is an essential component of antiviral immunity. For many viral infections, CD8 T cells are a necessary line of defense for complete virus clearance. However, for certain viral infections such as those caused by human immunodeficiency virus (HIV), hepatitis C or B virus (HCV, HBV) and herpes viruses (CMV, EBV, HSV) in humans and lymphocytic choriomeningitis virus (LCMV) Clone 13 (Cl13) in mice, the virus is able to evade immune detection and can persist in a chronic state within the host. Some types of chronic viral infections (e.g., HIV, HCV, LCMV Cl13) can lead to a state of virus-specific CD8 T cell dysfunction known as exhaustion, in which certain effector functions including proliferation, viability and cytokine production are reduced. The molecular mechanism(s) that regulate/cause CD8 T cell exhaustion are less well understood. Recent work has demonstrated a pivotal role for the PI3K/AKT/mTOR pathway in regulating multiple aspects of T cell biology, including: growth, proliferation, differentiation, function, and metabolism. PI3K/AKT/mTOR signaling results the differentiation of effector T cells and the acquisition of an anabolic metabolic state that is primarily fueled by glycolysis. On the other hand, the generation of memory cells is enhanced by limiting this pathway, and is associated with an increase fatty acid oxidation (catabolic). AMP-kinase negatively regulates PI3K/AKT/mTOR signaling, and promotes a catabolic metabolic state. Our overall hypothesis is that during chronic viral infection, CD8 T cells are unable to maintain an anabolic state and reside instead in a catabolic state, and that this is the root cause of T cell exhaustion. This metabolic dysfunction stems either from reduced PI3K/AKT/mTOR or increased AMPK/FOXO activity, or both. In this grant, we aim to test the hypothesis that the PI3K/AKT/mTOR signaling pathway is essential for maintaining T cell survival and function during chronic viral infection. PUBLIC HEALTH RELEVANCE: Chronic viral infections such as HIV, HCV, and HBV in humans and LCMV Cl13 in mice can often lead to a progressive loss of CD8 T cell function known as exhaustion, which hinders viral clearance and precludes the development protective antiviral immunity in the form of CD8 T cell memory. Our goal is to understand how signaling and metabolic pathways are integrated to cause to CD8 T cell exhaustion. Insight gained from these studies could lead to new therapies or vaccines that restore virus-specific CD8 T cell function and protective antiviral immunity, and would have a significant impact on improving human health.